The present invention relates to controlled, usually delayed release formulations, especially compositions that are suitable for delivering an active ingredient to the colon.
Compositions comprising amylose have been used in the preparation of dosage forms that can be used to deliver an active ingredient to the colon. The preparation of such dosage forms is described in U.S. Pat. No. 5,294,448 and involves contacting an active ingredient with a solution or dispersion of amylose formed from an aqueous amylose-butanol complex at a temperature in excess of 60xc2x0 C. to form a film and drying that film. Temperatures in excess of 60xc2x0 C. are considered to be essential in order to maintain or melt respectively the amylose in the solution or dispersion that comprises the film-forming composition. When the compositions are cooled the amylose in the films formed therefrom is in the glassy state.
Glassy amylose is one of the amorphous forms of amylose, the other being rubbery amylose. The rate of cooling and drying of the amylose film is considered to be important in the preparation of amylose films. If the rate of cooling is too low, crystalline regions of amylose are formed. If the quantity of water within the film exceeds a certain amount, the amylose may be formed in the rubbery form. Both crystalline and rubbery amylose are not digestible in the Gastro-Intestinal (GI) tract and are not considered to be suitable for the preparation of formulations for use in the delivery of an active material to the colon. In contrast glassy amylose has been found to be resistant to attack by the xcex1-amylases present in the small intestine but is degraded by the microflora present in the colon. These properties mean that it is particularly suitable for the preparation of dosage forms that can be used to deliver an active ingredient to the colon.
However, coats or films comprising purely glassy amylose have been found to swell in an aqueous environment and these swollen films are unable to retain their structural integrity when subject to mechanical stresses such as those experienced by the dosage form on its passage through the GI tract. Films or coats comprising amylose only are therefore unsuitable for the preparation of dosage forms for use in colonic delivery.
In order to overcome the disadvantages associated with films comprising amylose only, mixed compositions comprising amylose and a film-forming polymer have been prepared. See for example U.S. Pat. No. 5,294,488. The presence of a film-forming polymer prevents or limits the degree to which the amylose swells and confers some structural integrity on the film during its passage through the GI tract. Further ingredients such as water-soluble plasticisers may be added to the composition to assist in the formation of the final film or coat.
As with the preparation of xe2x80x9camylose onlyxe2x80x9d films, the preparation of films from the mixed film-forming composition required that the composition be contacted with the active ingredient at a temperature in excess of 60xc2x0 C. As before, this was in order to ensure that the amylose present in the composition was either completely solvated or in a melted form prior to the coating step. Upon drying the film, the amylose is preferably present in the glassy state. Coats or films comprising rubbery amylose may be formed but require the presence of porosity enhances in order to facilitate release of active material.
The formation of dosage forms in accordance with the method described in U.S. Pat. No. 5,294,448 has been found to be completely satisfactory for the preparation of dosage forms in which the active material is not temperature sensitive, but cannot be used for active materials that are thermolabile at temperatures above 60xc2x0 C. There is, therefore, a need for a method of coating, active materials for the preparation of dosage forms in which the active material is thermolabile above 60xc2x0 C. The present invention addresses, at least in part, that problem.
The present inventors have surprisingly found that a film-forming composition can be prepared which can be used to coat active materials at temperatures of less than 60xc2x0 C. Surprisingly the structural integrity of the films formed is substantially retained during their passage through the GI tract. By retention of structural integrity, it should be understood that the coat or film does not substantially swell and is retained by the active material on its passage through the GI tract. However, parts of the film may be lost, weakened or degraded at certain points in the GI tract as will be described herein below. These films are also unexpectedly resistant to digestion in both the stomach and the small intestine, but are degraded by the microflora present in the colon.
A first aspect of the invention provides a method of coating an active material or a formulation containing an active material comprising the steps of contacting an active material or formulation containing it at a temperature of less than 60xc2x0 C. with a film-forming composition comprising an aqueous dispersion of an amylose-alcohol complex, an insoluble film-forming polymer and a plasticiser, coating being carried out at a temperature of less than 60xc2x0 C. The coating step may suitably be carried out at a temperature of between 5 and 50xc2x0 C., preferably between 20 and 40xc2x0 C., more preferably between 30 and 40xc2x0 C. and especially between 35 and 37xc2x0 C. As indicated above, coatings formed according to the first aspect of the invention are surprisingly able to retain their structural integrity during their passage through the GI tract. They are substantially resistant to digestion in both the stomach and the small intestine but are degraded by the microflora present in the colon.
By the term xe2x80x9cfilm-formingxe2x80x9d it is to be understood that the composition is able to form a coat or a film upon contact with the active material (or a formulation containing the active material) that solidifies upon drying. The structural integrity of the film is substantially retained during its passage through the GI tract. The film or coat is also able to substantially resist digestion in the stomach and small intestine but is degraded by the microflora of the colon.
It is also believed that the films or coatings formed using the method of the present invention comprise substantially homogeneous mixtures of amylose and an insoluble cellulosic or acrylic polymer. The term homogeneous includes films comprising distinct regions of amylose randomly dispersed in an insoluble cellulosic polymer matrix as well as films in which the dispersion is such that the regions of amylose are indistinguishable from an insoluble cellulosic polymer matrix material for example.
The term xe2x80x9cactive materialxe2x80x9d applies to any material which is or may be sensitive to temperatures above low ambient, for example 20 to 40xc2x0 C., but also includes materials that are not degraded at temperatures outside this range. The active material could, for example, be a foodstuff or a pharmaceutical. It particularly includes any compound or composition useful in human or veterinary medicine, in therapy or diagnosis.
Preferred active materials include therapeutically active ingredients that find application in treating diseases of the colon or diseases the therapeutic management of which is best effected via the colon. Such diseases include, but are not limited to, cancer of the colon, irritable bowel syndrome (IBS) and Crohn""s disease.
It will be appreciated that the active material may be mixed with other carrier materials suitable to a particular use. Thus, particularly for therapeutic use, the active material will often be mixed with one or more of a bulking agent and a lubricant, for example lactose and magnesium stearate, respectively. Dosages of active materials for therapeutic use will be as disclosed in the literature, for example in the ABPI data sheet compendium, or may sometimes be less owing to the more efficient delivery of the material. The active in material may be used together with one or more additional active materials.
The invention also includes a the coating of a formulation containing an active material e.g. a dosage form containing a coated or uncoated active material such as, pellets, capsules or tablets.
The active material, either alone or in admixture with a carrier, is coated with a coating material at temperatures that do not destroy the integrity of the substrate but are greater than the minimum film-forming temperature for the composition
The term xe2x80x9cdosage formxe2x80x9d should be understood to include any solid dosage form that may be administered to a human or animal patient or that may be used in an agricultural or industrial application, without limitation. Examples of suitable dosage forms include tablets, pellets and capsules.
In addition to their value in achieving a delayed release of therapeutic agents, particularly in their delivery to the colon as discussed above, the compositions of the invention are useful in diagnosis, for example in delivering agents such as contrast media to the colon in connection with X-ray and NMR imaging techniques. An alternative diagnostic area lies in the delivery of potentially allergenic foodstuff components to the colon for the diagnosis of allergies.
By the term xe2x80x9cinsoluble polymerxe2x80x9d it is to be understood to mean that the polymers present in the film-forming composition should be water-insoluble as well as insoluble in aqueous acidic and alkaline media. Thus the solubility of the film-forming polymer in water at room temperature should be less than 10% w/v. The level of solubility in aqueous acidic media at pH 1 should be less than 1% w/v and in aqueous alkaline media at a pH of 7.2 should be less than 1% w/v. Any pharmaceutically or agriculturally acceptable insoluble polymer may be used in the preparation of the film-forming compositions of the invention. Preferred film-forming polymers include water-insoluble cellulosic or acrylic polymers. Shellac may also be used. Mixtures of different polymers may be used. The use of ethyl cellulose as a film-forming polymer is especially preferred.
The term xe2x80x9cacrylic polymerxe2x80x9d includes both acrylate and methacrylate polymers and especially co-polymers thereof, the esterifying groups in these polymers being of various types, for example C1-18 alkyl groups. Preferred forms of acrylate polymer are those marketed under the TradeMark Eudragit, particularly Eudragit RL and RS whose degradation is independent of pH.
A preferred molecular weight range for the film-forming cellulose materials is 42,000 to 280,000 g/mol (or daltons) and for the film-forming acrylic polymer materials is 150,000 to 250,000 g/mol (or daltons) but materials with molecular weights outside these ranges, for example of a higher molecular weight, can be used where appropriate.
The degradation of the cellulose materials in vivo is in general not pH dependent and it is preferred that this is also true for the acrylate materials. This may be achieved by the selection of appropriate forms of side chain on the main polymer chain, in particular of side chains that have a low negative charge or preferably which are uncharged, as opposed to those having a positive charge. Preferred forms of acrylate polymers are those marketed by Dumas (UK) Limited of Tunbridge Wells under the TradeMark Eudragit, particularly the materials Eudragit L whose degradation is independent of pH. A preferred cellulose polymer, ethyl cellulose, is marketed by the Dow Chemical Company and Shinetsu Chemical Products under the TradeMark Ethocel.
Other preferred forms of cellulosic polymers include ethyl cellulose pseudolatex solutions, which are sold under the TradeMarks Surelease(copyright) and Aquacoat(copyright).
Surelease(copyright) is prepared by forming a homogeneous melt of ethyl cellulose (20 cPs, USNF), the plasticiser dibutyl sebacate and an oleic acid stabiliser and dispersing said melt in ammoniated water to give a dispersion containing 25% w/w solids. Hydrogenated coconut oil may also be used as a plasticiser instead of or in addition to dibutyl sebacate. The plasticiser (dibutyl sebacate and/or hydrogenated coconut oil) is generally present in a total amount comprising 20 to 24% by weight of the ethyl cellulose polymer, preferably 21 to 22% by weight. The process of adding a plasticiser to a film-forming polymer prior to dispersion in water is known as pre-plasticisation and the term xe2x80x9cpre-plasticised polymerxe2x80x9d should be understood accordingly. Plasticisation may also be achieved by the addition of a plasticiser to the aqueous dispersion of the insoluble polymer.
Aquacoat(copyright) is manufactured by dissolving ethyl cellulose (10 cPS, premium grade) in a water immiscible solvent; emulsifying in water in the presence of an anionic surfactant and a stabiliser; homogenising the crude emulsion and removing the organic solvent to give an aqueous pseudolatex dispersion containing 30% w/w solids. The commercially available Aquacoat(copyright) dispersion contains no plasticiser.
Formation of an aqueous dispersion of an amylose-alcohol complex is well known and is described in U.S. Pat. No. 5,294,448 and also by Milojeric et al, in J. Controlled Release, 38 (1996) 75-84 and requires the precipitation from solution of amylose through the formation of an amylose-alcohol complex. Any C3-6 alcohol may be used to precipitate the amylose. The use of butan-1-ol to precipitate amylose from solution is particularly preferred.
The dosage forms prepared in accordance with the first aspect of the invention are dried at a temperature of between 5 and 40xc2x0 C., preferably 20 to 40xc2x0 C. and especially between 33 and 37xc2x0 C. over a period of between 0 and 2 hours, preferably between xc2xd and 1 hour and especially for between xc2xd and xc2xe hour. The temperature at which the dosage formed is dried will depend, in part, upon the temperature at which the coating was carried out and is preferably no higher than the coating temperature. The time for which the dosage forms are dried will depend upon factors such as the initial concentration of the film forming composition and the drying temperature selected. Long drying times should be avoided as these may result in crystalline regions within the final film. Shorter drying times ensure that the amylose is retained in the amorphous form in the final form, preferably in the glassy form.
The film forming composition suitably contains between 1 and 12% w/w of amylose-alcohol complex, between 7 and 30% w/w of the insoluble polymer and between a total of 20 and 40% of plasticiser by weight of the insoluble polymer. The film-forming compositions are conveniently prepared by admixing an aqueous dispersion of an amylose-alcohol complex with an aqueous dispersion of the insoluble polymer and plasticiser. Typically the aqueous dispersion of the insoluble polymer is pre-plasticised by rapid, shear-mixing with an aqueous dispersion of the plasticiser. A surfactant such as Tween 80(trademark) may be added in quantities of about 0.1% by weight of the dispersion in order to facilitate pre-plasticisation of the insoluble polymer. Alternatively the plasticiser may be mixed directly with the ethyl cellulose polymer before dispersion.
The actual concentration of the film-forming polymer used for the coating step will generally depend upon the coating methods employed. In general film forming compositions of higher concentration are required for casting methods whereas compositions of lower concentration are required for spraying methods. Compositions used for casting may comprise 22 to 80% solids by weight of the final composition whereas compositions used for spraying may comprise between 15 and 25% solids by weight, preferably between 16 and 22% w/w.
The aqueous dispersion of the amylose-alcohol complex is preferably a dispersion of an amylose-butanol complex. The concentration of the amylose-butanol complex in the dispersion may be in the range of 3 to 12% by weight of the final dispersion, preferably between 4 and 8% by weight, more preferably between 5 and 7% w/w and especially 6% w/w.
The concentration of the aqueous dispersion of the insoluble polymer may be in the range 15 to 30% by weight of the final dispersion, preferably 17 to 28%, more preferably 20 to 25% w/w and especially 25% w/w. Dispersions having concentrations outside these ranges may be used. It is preferred to use the commercially available ethyl cellulose dispersions Surelease(copyright) and Aquacoat(copyright) in the method of the present invention.
The relative proportions in which the components of the film-forming composition are mixed will depend upon the desired ratio of insoluble polymer to amylose in the final film. In general it is to be understood that the ratio of insoluble polymer to amylose in the film-forming composition is taken to be the same as that in the final film or coat formed. It is preferred that the ratio of insoluble polymer to amylose is in the range 1:1 to 7:1, preferably in the range 1:1 to 5:1 and especially in the range 3:2 to 2:1. The use of film-forming compositions having an insoluble polymer to amylose ratio outside this range, for example, 10:1 may be envisaged in certain circumstances. Particularly good results have been achieved using film-forming compositions having an insoluble polymer to amylose ratio of 5:2 and 3:2 respectively.
It is preferred that the concentration of amylose in the film-forming compositions used in the present invention is sufficient such that the amylose is in the glassy form in the films formed.
In its glassy state the structure of the polymer is generally rigid; regions of increased polymer chain movement and polymer elasticity are found in the rubbery state. Amylose exists in its glassy state below the glass transition temperature (Tg). Rising through this temperature, there is a sharp increase in the heat capacity of the amylose of 0.5xc2x10.15 Jgxe2x88x921Kxe2x88x921 (joules per gram per degree Kelvin). This heat capacity increment allows the Tg to be identified and can be measured by differential scanning calorimetry. Examples of procedures for obtaining Tg values and earlier literature references to such procedures are given in Orford et al, Int. J. Biol. Macromol. 1989, 11, 91.
The particular Tg of amylose in a given film or coat formed from the film forming composition of the present invention depends upon its purity and other properties. Thus, for example, the theoretical Tg for pure, dry amylose may be predicted to be 210xc2x0 C. but the presence of water depresses this figure: with 10% w/w of water the Tg is 80xc2x0 C. and at 20% w/w of water it is 7xc2x0 C. It has been found that xcex1-amylolytic enzymes do not readily degrade glassy amylose and this effect is still apparent at up to 20xc2x0 C. above the Tg. Such materials have been found to be sufficiently insoluble in aqueous media over the pH range 1-9 at 37xc2x0 C. to be resistant to degradation in the stomach or intestine. They are, however, degraded by the enzymes produced by the faecal micro-organisms present in the colon. As indicated, the ability of glassy amylose to provide the required delayed release characteristics is not lost immediately the glassy amylose passes through the Tg and amylose which has been produced in the glassy condition at temperatures less than the Tg may therefore then be utilised at the Tg or at temperatures slightly higher than the Tg as well as at temperatures less than the Tg, whilst still retaining its glassy properties. However, the glassy amylose preferably used in the present invention has a Tg of no more than 20xc2x0 C. below the temperature at which use of the composition is envisaged i.e. at body temperature of 37xc2x0 C. Thus the Tg of the amylose will in the films or coats formed conveniently be 17xc2x0 C. or higher and is preferably at least 30xc2x0 C. or, more preferably at least about 40xc2x0 C. The Tg can be predetermined by controlling the amount of water in it. This can be achieved by varying the concentration of the amylose solution, which is cooled or sprayed, and by drying the resulting gel.
The ultimate test of the suitability of a particular sample of amylose under any given conditions is its ability to resist hydrolytic degradation under aqueous conditions, particularly at a pH of 1-9 and a temperature of 37xc2x0 C., and conveniently also to resist enzymatic degradation in the presence of the digestive enzymes such as normally occur in the stomach and the small intestine, but to undergo enzymatic degradation in the presence of amylose-cleaving enzymes such as are provided by the microbial flora normally present in the large intestine.
It is preferred therefore that the amylose in the film or coat formed is substantially free, i.e. contains no more than 20% by weight and preferably no more than 10% or 5% by weight, of any material which is susceptible to digestion in the stomach or small intestine. In particular the glassy amylose preferably contains no more than 10% or 5% by weight of amylopectin, for example 1 or 2% or less, and conveniently also of any material containing glucoside linkages of the type found in amylopectin. It will be appreciated that the presence of other materials in admixture with the amylose will detract from the selective nature of the degradation of this material as between the stomach and small intestine and the large intestine.
A convenient test for the purity of the amylose in the film or coat formed is provided by its iodine binding ability in a standard assay procedure such as is described by Banks et al, Starke, 1971, 23, 118. Thus pure, underivatised amylose binds with iodine to a level of about 19.5% w/w (i.e. 19.5xc2x10.5% w/w) whereas the other main starch polysaccharide, amylopectin, binds less than 2.0% w/w and derivatisation of the amylose will also reduce this binding ability. Conveniently therefore the amylose used in the present invention binds with iodine to a level of 15.0%xc2x10.5% w/w, or above, preferably to a level of 18.0%xc2x10.5% w/w or above, and particularly to a level of 19.5xc2x10.5% w/w.
It is preferred that the molecular weight of the amylose used in the invention is at least 20000 g/mol (daltons) with weights in the range of 100000 to 500000 g/mol being especially preferred. It will be appreciated that the weight of amylose used in the coating composition will depend upon the particular requirements and circumstances and may dictate that amylose having a molecular weight either below or above those weight ranges herein above described may also be advantageously used.
The release characteristics of a dosage form formed from the method of the present invention may be controlled by variations in the nature of the film-forming composition and coating conditions. The release of an active material from a dosage form has been found to be dependent on, without limitation, the ratio of insoluble polymer to amylose in the coat, the amount of plasticiser used, the coat thickness employed and the solubility characteristics of the active material coated.
Compositions having a high insoluble polymer to amylose ratio, such as 10:1 or 7:1 have been found to give rise to films that significantly retard release of an active material. Compositions having a low insoluble polymer to amylose ratio of 1:1 have been found to form films that are less able to retard drug (active material) release to a significant extent. Compositions having an insoluble polymer to amylose ratio of between 5:2 and 3:2 have been found to form films that are able to substantially inhibit release of drug during the period in which the dosage form is in the stomach and small intestine, but allow dissolution or release of the drug subsequently.
The rate of release of an active material from a dosage form has been found to be dependent on the thickness of the coat or film-formed with the dissolution of active material being retarded to a greater extent with a thicker film. The thickness of the film is suitably chosen to prevent the release of the active material during the passage of the dosage form through the stomach and small intestine but to allow release thereof in the colon. In practice the chosen thickness of the coat will also depend upon the nature of the film-forming composition as well as the solubility of the active material that it is desired to coat. It is preferred to use thicker coats when the ratio of insoluble polymer to amylose is low or when the solubility of the active material is high. Thinner coats are preferred when the ratio of insoluble polymer to amylose is high or the solubility of the active material is low.
The plasticiser used in the film-forming composition is preferably hydrophobic in nature, although hydrophilic plasticisers may be used where they do not inhibit the film forming properties of the composition. The amount of plasticiser added to the dispersion of the insoluble polymer will depend upon whether or not the insoluble polymer has been pre-plasticised, that is to say whether or not a plasticiser has been added to the insoluble polymer prior to the formation of the dispersion. If the insoluble polymer has not been pre-plasticised, between 20 and 40% of plasticiser by weight of insoluble polymer may be added to the dispersion of insoluble polymer prior to its incorporation in the film forming composition, preferably between 24 and 36% by weight. If the insoluble polymer has been pre-plasticised, between 5 and 15% of plasticiser by weight of pre-plasticised insoluble polymer may be added to the dispersion of insoluble polymer prior to its incorporation in the film forming composition. The actual amount of additional plasticiser added to a pre-plasticised insoluble polymer will depend upon the extent to which the insoluble polymer has been pre-plasticised and it is preferred that the total amount of plasticiser present in the dispersion (amount of plasticiser present in pre-plasticised polymer+any additional plasticiser) does not exceed 40% by weight of the weight of the insoluble polymer. If inadequate plasticiser is present (less than 20%) the film is characterised by the present of fragments, is brittle and is of insufficient strength. If too much plasticiser is present (more than 40%) the film is characterised by a wrinkly appearance and the polymer is in a semi-solid state. As before, such films are of insufficient strength to withstand the mechanical forces experienced by a dosage form during this passage through the GI tract. Film-forming compositions comprising between 24 and 36% of plasticiser by weight of insoluble polymer give a smooth, clear, continuous films that are of good mechanical strength and are associated with dissolution profiles which render them suitable for use in the colonic delivery of an active material.
The amount of plasticiser present in the film has also been found to effect the dissolution profile of an active material. A high concentration of plasticiser is associated with a slower rate of release of the active material from the dosage form. It will therefore be appreciated that the amount of plasticiser included in the film-forming compositions will depend, in part, upon the relative quantities of insoluble polymer and amylose present in the film as well as the thickness of the coat formed. If the ratio of insoluble polymer to amylose is high less plasticiser is required. Less plasticiser is also required if a large coat thickness is employed.
Examples of plasticiser that may be used in the film forming compositions used in the method of the present invention include dibutyl sebacate, triethyl citrate, triacetin, acetyl tributyl citrate, hydrogenated coconut oil and tributyl citrate. If the insoluble polymer of choice is Surelease(copyright) the preferred plasticisers are dibutyl sebacate, acetyl tributyl citrate, hydrogenated coconut oil and tributyl citrate, especially dibutyl sebacate. If Aquacoat is used as the insoluble polymer dispersion the preferred plasticisers are dibutyl sebacate, triethyl citrate, triacetin, acetyl tributyl citrate and tributyl citrate. Dibutyl sebacate and tributyl citrate are especially preferred when Aquacoat(copyright) is used.
It will be appreciated that the method according to the first aspect of the invention is particularly suitable for the preparation of dosage forms comprising a thermolabile active ingredient. A second aspect of the invention, therefore, provides a dosage form comprising a thermolabile active ingredient, the dosage form being coated in accordance with the method according to the first aspect of the invention. The active ingredient may be present in admixture with any suitable carrier or excipient or any other active ingredient. By the term xe2x80x9cthermolabilexe2x80x9d it is to be understood that the active materials is unstable and has a tendency to degrade at temperatures greater than 60xc2x0 C., preferably 50xc2x0 C. and especially 40xc2x0 C.
It is believed that the film-forming compositions comprising a hydrophobic plasticiser used in the method according to the first aspect of the invention are new per se. A third aspect of the present invention provides a composition comprising an aqueous dispersion of an amylose-alcohol dispersion, an insoluble film forming polymer and a hydrophobic plasticiser. The nature and relative quantities of the components of the composition have been discussed herein above.
As indicated previously, the dosage forms prepared in accordance with the first aspect of the invention find particular application for use in therapy, particularly for use in diseases of the colon and conditions, the therapeutic management of which is best effected via the colon. The present invention therefore provides the use of a dosage form according to the second aspect of the invention for use in therapy.
The present invention also provides a method of therapy, said method comprising the administration to a patent of a dosage form prepared in accordance with the first aspect of the invention.
The invention will now be described with reference to the following, non-limiting, examples. Variations of these examples falling within the scope of the invention will be apparent to a person skilled in the art.